US20070172521A1 - Levetiracetam formulations and methods for their manufacture - Google Patents
Levetiracetam formulations and methods for their manufacture Download PDFInfo
- Publication number
- US20070172521A1 US20070172521A1 US11/371,128 US37112806A US2007172521A1 US 20070172521 A1 US20070172521 A1 US 20070172521A1 US 37112806 A US37112806 A US 37112806A US 2007172521 A1 US2007172521 A1 US 2007172521A1
- Authority
- US
- United States
- Prior art keywords
- composition
- levetiracetam
- glidant
- free
- percent
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 104
- 229960004002 levetiracetam Drugs 0.000 title claims abstract description 77
- 238000000034 method Methods 0.000 title claims abstract description 21
- HPHUVLMMVZITSG-ZCFIWIBFSA-N levetiracetam Chemical compound CC[C@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-ZCFIWIBFSA-N 0.000 title claims abstract 33
- 238000009472 formulation Methods 0.000 title description 21
- 238000004519 manufacturing process Methods 0.000 title description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 26
- 239000002552 dosage form Substances 0.000 claims description 16
- 239000002245 particle Substances 0.000 claims description 15
- 239000002775 capsule Substances 0.000 claims description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 11
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- 238000003556 assay Methods 0.000 claims description 6
- 239000003086 colorant Substances 0.000 claims description 6
- 235000019359 magnesium stearate Nutrition 0.000 claims description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 5
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 239000007788 liquid Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 229940069328 povidone Drugs 0.000 claims description 5
- 239000004408 titanium dioxide Substances 0.000 claims description 5
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 4
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 4
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000008213 purified water Substances 0.000 claims description 4
- 238000005550 wet granulation Methods 0.000 claims description 4
- 229920002261 Corn starch Polymers 0.000 claims description 3
- 239000008120 corn starch Substances 0.000 claims description 3
- 238000009826 distribution Methods 0.000 claims description 3
- 238000007908 dry granulation Methods 0.000 claims description 3
- 238000005469 granulation Methods 0.000 claims description 3
- 230000003179 granulation Effects 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 3
- 229940057948 magnesium stearate Drugs 0.000 claims description 3
- 239000008109 sodium starch glycolate Substances 0.000 claims description 3
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 3
- 229920003109 sodium starch glycolate Polymers 0.000 claims description 3
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000003801 milling Methods 0.000 claims 2
- HPHUVLMMVZITSG-LURJTMIESA-N levetiracetam Chemical compound CC[C@@H](C(N)=O)N1CCCC1=O HPHUVLMMVZITSG-LURJTMIESA-N 0.000 description 45
- 239000008187 granular material Substances 0.000 description 24
- 239000003826 tablet Substances 0.000 description 24
- 239000000463 material Substances 0.000 description 10
- 239000000843 powder Substances 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 8
- 239000007884 disintegrant Substances 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 5
- 239000003085 diluting agent Substances 0.000 description 5
- 239000000314 lubricant Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000011230 binding agent Substances 0.000 description 4
- 239000002671 adjuvant Substances 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 239000008247 solid mixture Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- XPCTZQVDEJYUGT-UHFFFAOYSA-N 3-hydroxy-2-methyl-4-pyrone Chemical compound CC=1OC=CC(=O)C=1O XPCTZQVDEJYUGT-UHFFFAOYSA-N 0.000 description 2
- 239000004097 EU approved flavor enhancer Substances 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 229920002562 Polyethylene Glycol 3350 Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- -1 e.g. Substances 0.000 description 2
- CBOQJANXLMLOSS-UHFFFAOYSA-N ethyl vanillin Chemical group CCOC1=CC(C=O)=CC=C1O CBOQJANXLMLOSS-UHFFFAOYSA-N 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 235000019264 food flavour enhancer Nutrition 0.000 description 2
- 229960003943 hypromellose Drugs 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 238000007873 sieving Methods 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- YIKYNHJUKRTCJL-UHFFFAOYSA-N Ethyl maltol Chemical compound CCC=1OC=CC(=O)C=1O YIKYNHJUKRTCJL-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- HYMLWHLQFGRFIY-UHFFFAOYSA-N Maltol Natural products CC1OC=CC(=O)C1=O HYMLWHLQFGRFIY-UHFFFAOYSA-N 0.000 description 1
- 241000238367 Mya arenaria Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- FAAHNQAYWKTLFD-SSDOTTSWSA-N [H][C@@](C)(CC)N1CCCC1=O Chemical compound [H][C@@](C)(CC)N1CCCC1=O FAAHNQAYWKTLFD-SSDOTTSWSA-N 0.000 description 1
- 239000011149 active material Substances 0.000 description 1
- 239000012615 aggregate Substances 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 229960003965 antiepileptics Drugs 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229940078456 calcium stearate Drugs 0.000 description 1
- 239000007963 capsule composition Substances 0.000 description 1
- 239000004359 castor oil Substances 0.000 description 1
- 235000019438 castor oil Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 239000011436 cob Substances 0.000 description 1
- 239000013065 commercial product Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 229940093503 ethyl maltol Drugs 0.000 description 1
- 229940073505 ethyl vanillin Drugs 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 229960002598 fumaric acid Drugs 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 description 1
- 229940075507 glyceryl monostearate Drugs 0.000 description 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 229940062717 keppra Drugs 0.000 description 1
- 229940043353 maltol Drugs 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 229940057838 polyethylene glycol 4000 Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate Substances 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 229960004274 stearic acid Drugs 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 229940033134 talc Drugs 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 1
- 229940057977 zinc stearate Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Definitions
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and/or a care giver to handle.
- Diluents useful in the present invention include those diluents known in the art that do not function as glidants. Diluents that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the diluent to function as a glidant.
Abstract
Substantially glidant free levetiracetam compositions, pharmaceutical compositions incorporating substantially glidant free levetiracetam compositions, and methods of preparing such compositions are provided.
Description
- The present invention relates to stable substantially glidant free levetiracetam compositions, to pharmaceutical compositions and pharmaceuticals comprising the substantially glidant free levetiracetam compositions of the invention as the active ingredient, and to methods of preparing the compositions of the invention.
-
- Levetiracetam tablets are commercially available under the trade name KEPPRA®, and, typically, comprise colloidal silicon dioxide as a glidant, as well as corn starch, hydroxypropyl methylcellulose, magnesium stearate, polyethylene glycol 4000, povidone, talc, titanium dioxide, and coloring agents.
- Glidant materials are generally added to pharmaceutical compositions following granulation and drying of the particles to facilitate the flow of the dried granules. Therefore, for use as a glidant, such materials are extra-granular materials. Glidant materials, especially colloidal silicon dioxide, are typically extremely fluffy and bulky, and often require a sieving stage. During sieving, a significant amount of airborne particles is often produced. Such airborne particles are a potential safety hazard, and, thus, require the use of safety equipment and other safety precautions by workers handling the materials.
- Moreover, because particles of glidant materials, such as colloidal silicon dioxide, are extremely small, the total surface area of a sample of such a material is extremely large, relative to the volume of the sample. It is believed that the small size and high surface area are possible sources of instability of the active ingredients of a formulation comprising such a glidant. The instability may be caused by a direct interaction between the glidant particles and the active ingredient, or the glidant may act as a catalyst, facilitating interactions that result in the instability of the active ingredient.
- Therefore, to reduce hazards to workers and improve the stability of levetiracetam in pharmaceutical compositions, a need exists for substantially glidant free levetiracetam formulations and methods of preparing such formulations. The present invention provides such formulations and methods.
- The present invention is directed to stable levetiracetam tablet formulations that are preferably substantially free of glidants and to methods of preparing substantially glidant free levetiracetam formulations and pharmaceutical compositions comprising substantially glidant free levetiracetam formulations. The substantially glidant free levetiracetam formulations of the invention may be formed into tablets that are stable and easily handled.
- The present invention provides robust, high concentration, substantially glidant free levetiracetam pharmaceutical compositions, preferably, comprising at least about 60 percent levetiracetam, more preferably, at least about 70 percent levetiracetam, and, most preferably, from about 70 to about 95 percent levetiracetam. Substantially glidant free levetiracetam compositions of the invention may comprise one or more other pharmaceutically acceptable excipients, such as corn starch, povidone, croscarmellose sodium, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, coloring agents, and mixtures thereof. Where an excipient used in a formulation in accordance with the invention is a substance that can function as a glidant if mixed with granules of the substantially glidant free levetiracetam compositions of the invention, the substance is either incorporated into the granules of the composition, where it cannot function as a glidant, and, thus, is not a glidant, or is not present in an amount that allows the excipient to function as a glidant. Substantially glidant free levetiracetam formulations in accordance with the present invention are preferably formulated into pharmaceutical formulations, such as conventional dosage forms, e.g., tablets and capsules. The preferred substantially glidant free levetiracetam dosage form is a tablet.
- Substantially glidant free levetiracetam formulations for use in tablets may be dry-granulated or wet-granulated before tableting, or the tablet blends may be directly compressed. For pharmaceuticals, the type of processing utilized often depends upon the properties of the drug, the chosen excipients, and the dosage form, e.g., particle size, blending compatibility, density, and flowability. For levetiracetam tablets, granulation is preferred, and wet granulation is most preferred. Tablets in accordance with the invention may be coated to facilitate swallowing and/or to enhance the appearance of the tablet.
- As used herein, the term “glidant” refers to a material that, when added to a dried granulated pharmaceutical composition in a sufficient amount, facilitates the flow of the granules during processing. As glidants are generally added to dried, granulated compositions, glidants may be referred to as extra-granular materials.
- As used here in the term “substantially glidant free levetiracetam” refers to a levetiracetam formulation or composition that is free of all but trace amounts of any extra-granular material that can function as a glidant. That is, extra-granular materials that can function as a glidant are not present in the substantially glidant free levetiracetam compositions of the invention in an amount that will function as a glidant for a granulated composition. Glidants are typically added to pharmaceutical compositions to improve the flowability of a non-compacted solid composition, and to improve the accuracy of dosing. The addition of glidants is not necessary in the substantially glidant free levetiracetam compositions of the invention to improve flowability.
- As used herein, the term “high dosage levetiracetam” preferably refers to a levetiracetam dosage form of at least about 250 mg, more preferably, at least about 500 mg, and, most preferably, at least about 750 mg. Preferably, substantially glidant free levetiracetam compositions of the invention are formed into film coated tablets, and, more preferably, comprise about 250, about 500, or about 750 mg of levetiracetam per tablet.
- Substantially glidant free levetiracetam tablets in accordance with the invention can be dry-granulated or wet-granulated before tableting, or directly compressed into tablets. Preferably, in accordance with the method of the invention, levetiracetam and, optionally, at least one excipient is wet-granulated, where the preferred granulating liquid is purified water. The granulated material is then preferably dried, milled, and, optionally, blended with one or more excipients. Most preferably, the final blend is then compressed into tablets and coated. The granulated material optionally blended with one or more additional excipients can also be placed into an ingestible capsule.
- In addition to the active ingredient, levetiracetam, pharmaceutical compositions of the substantially glidant free levetiracetam of the present invention may contain one or more excipients or adjuvants. Selection of excipients and the amount of such excipients used may be readily determined by a formulation scientist based upon experience and consideration of standard procedures and reference works in the field. Excipients and adjuvants that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the excipient or adjuvant to function as a glidant.
- Diluents increase the bulk of a solid pharmaceutical composition, and may make a pharmaceutical dosage form containing the composition easier for the patient and/or a care giver to handle. Diluents useful in the present invention include those diluents known in the art that do not function as glidants. Diluents that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the diluent to function as a glidant.
- Solid pharmaceutical compositions that are compacted into a dosage form, such as a tablet, may include excipients that facilitate binding the active ingredient and excipients together after compression. Useful binders include those binders known in the art that do not function as glidants. Binders that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the binder to function as a glidant.
- The dissolution rate of a compacted solid pharmaceutical composition in the patient's stomach may be increased by the addition of a disintegrant to the composition. Disintegrants useful in the invention include those disintegrants known in the art that do not function as glidants. Disintegrants that may function as a glidant are not present as extra-granular materials in the formulations of the invention in an amount that allows the disintegrant to function as a glidant.
- Solid compositions of the substantially glidant free levetiracetam of the invention include powders, granulates, aggregates, and compacted compositions. The dosages may be conveniently presented in unit dosage form, and prepared by any of the methods well-known in the pharmaceutical arts. Useful dosage forms of the substantially glidant free levetiracetam of the invention include, but are not limited to solid dosage forms, such as tablets, powders, and capsules.
- The dosage form of the present invention may be a capsule containing the composition, preferably a powdered or granulated solid composition of the invention, within either a hard or soft shell. The shell may be made from gelatin, and optionally contain a plasticizer, such as glycerin and sorbitol, and an opacifying agent or colorant.
- Flavoring agents and flavor enhancers make the dosage form more palatable to the patient. Common flavoring agents and flavor enhancers for pharmaceutical products that may be included in the composition of the present invention include maltol, vanillin, ethyl vanillin, menthol, citric acid, fumaric acid, ethyl maltol, and tartaric acid.
- A composition for tableting or capsule filling may be prepared by wet granulation. In wet granulation, some or all of the active ingredients and excipients in powder form are blended, and then further mixed in the presence of a liquid, typically water, that causes the powders to clump into granules. The granulate may be screened and/or milled, dried, and then screened and/or milled to the desired particle size. The granulate may then be tableted, or other excipients may be added prior to tableting, such as a lubricant.
- A tableting composition may be prepared conventionally by dry granulation. For example, the blended composition of the actives and excipients may be compacted into a slug or a sheet, and then comminuted into compacted granules. The compacted granules may subsequently be compressed into a tablet.
- As an alternative to dry granulation, a blended composition may be compressed directly into a compacted dosage form using direct compression techniques. The proper use of excipients in direct compression tableting is known to those skilled in the art of direct compression tableting.
- When a dosage form, such as a tablet, is made by the compaction of a powdered composition, the composition is subjected to pressure from a punch and dye. Some excipients and active ingredients have a tendency to adhere to the surfaces of the punch and dye, which can cause the product to have pitting and other surface irregularities. A lubricant can be added to the composition to reduce adhesion and ease the release of the product from the dye. Lubricants include magnesium stearate, calcium stearate, glyceryl monostearate, glyceryl palmitostearate, hydrogenated castor oil, hydrogenated vegetable oil, mineral oil, polyethylene glycol, sodium benzoate, sodium lauryl sulfate, sodium stearyl fumarate, stearic acid, talc, and zinc stearate. Lubricants that may function as a glidant are not present in the formulations of the invention in an amount that allows the lubricant to function as a glidant.
- A capsule filling of the present invention may comprise any of the aforementioned blends and granulates that were described with reference to tableting; however, they are not subjected to a final tableting step.
- The following non-limiting examples are merely illustrative of the preferred embodiments of the present invention, and are not to be construed as limiting the invention, the scope of which is defined by the appended claims.
-
Ingredient (mg/tablet) Part I: Levetiracetam 750.0 Povidone 40.0 Starch 90.0 Sodium Starch Glycolate 110.0 Part II: Magnesium Stearate 10.0 Part III: *OPADRY ® 03F23356 30.0 Total 1030.0
*Commercially available powder mix for coating comprising Hypromellose (HPMC); Titanium Dioxide; PolyEthyleneGlycol (PEG 3350); colorants
- The ingredients of Part I were granulated using purified water as a granulating liquid. The granulate was dried, milled and blended with the Part II ingredient. The final blend was compressed into tablets, and coated using the Part III material suspended in water.
-
Ingredient (mg/tablet) Part I: Levetiracetam 750.0 Povidone 24.0 Starch 102.0 Croscarmellose Sodium 111.0 Part II: Croscarmellose Sodium Magnesium Stearate 9.0 Part III: *OPADRY ® 03F23356 27.0 Total 1023.0
*Commercially available powder mix for coating comprising Hypromellose (HPMC); Titanium Dioxide; PolyEthyleneGlycol (PEG 3350); colorants
- The ingredients of Part I were granulated using purified water as a granulating liquid. The resulting granulate was dried, milled, and blended with the Part II ingredients. The final blend was compressed into tablets and coated using a suspension of the Part III material in water.
- As demonstrated by Examples 1 and 2, the exemplified formulations contain about 75 percent by weight of the active material in the tablet cores. The importance of flow properties cannot be over emphasized for such a high dose product. The flow properties of solids have an impact on encapsulation and tableting, as manufacturing processes require the flow of powder materials from a storage container to capsule filling injectors or tablet dies. The flow properties of solids also have influence on the uniformity of powders before tableting. Colloidal silicon dioxide is widely used as a glidant in capsule and tablet formulations improving the flow properties of the powders or granulates, but is not required in the substantially glidant free levetiracetam compositions of the invention. Therefore, the substantially glidant free levetiracetam compositions of the invention are substantially free of colloidal silicon dioxide.
- Preferably, the formulations of the invention have good flow properties, such that an analysis of the blend uniformity provides an assay of the blend between about 90 and 110 percent with an associated RSD of less than about 5 percent. More preferably, the assay of the blend is between about 95 and about 105 percent with an associated RSD of less than about 2 percent. Examples 1 and 2 demonstrate that substantially glidant free levetiracetam formulations in accordance with the invention have very good flow properties, uniform final blends, such that the assay is greater than about 98 percent, and the associated RSD is less than about 1 percent, and tablet cores, having acceptable physical properties, as shown in Table 1.
TABLE 1 Exp. Bulk Tapped Uniformity No. density density of blend Hardness Friability 1 0.6 g/ml 0.7 g/ml 98.4% RSD 0.6% 22-32 SCU± 0%
±SCU = Strong Cobb Units
- In order to avoid possible handling difficulties, the levetiracetam used preferably comprises particles having a particle size distribution such that d(0.1) is Not Less Than (NLT) about 0.6 μm, d(0.5) is from about 10 to about 30 μm, and d(0.9) is Not More Than (NMT) about 65 μm. In addition, the Bulk Density is NLT 0.2 g/cm3, and the Tapped Density is NLT 0.35 g/cm3. The levetiracetam used above had a particle size of about 50 μm. To minimize the impact of particle size on the levetiracetam release rate, a disintegrant was added intra- and extra-granularly. Although the resulting dissolution rate is somewhat slower than that of the commercial product, the product of present invention is found to be bio-equivalent to the marketed product in both fasting and food bio-equivalent studies.
- A stability test was performed on samples of Examples 1 and 2 initially after they were prepared and after storage under the accelerated conditions of a temperature of 40° C. and a relative humidity (RH) of 75 percent for 3 months. The HPLC method was employed for chemical analysis. A stability test was also conducted for the marketed product. The results are shown in Table 2.
TABLE 2 Exp. No. Initial Total +IDD result 3 mon. 40° C./75% RH 1 <0.05% <0.05% 2 0.06% <0.05% Com. Prod. <0.05% <0.05%
+IDD = Impurity and Degredants Determination
- While it is apparent that the invention disclosed herein is well calculated to fulfill the objects stated above, it will be appreciated that numerous modifications and embodiments may be devised by those skilled in the art. Therefore, it is intended that the appended claims cover all such modifications and embodiments as falling within the true spirit and scope of the present invention.
Claims (23)
1. A substantially glidant free levetiracetam composition, comprising levetiracetam and, optionally, an excipient, wherein the composition is substantially free of any extra-granular glidant.
2. The substantially glidant free levetiracetam composition of claim 1 , wherein the composition has a uniformity of blend, such that an assay of the blend is between 90 and 110 percent with an associated RSD of less than 5 percent.
3. The substantially glidant free levetiracetam composition of claim 1 , wherein the composition has a uniformity of blend, such that an assay of the blend is between 95 and 105 percent with an associated RSD of less than 2 percent.
4. The substantially glidant free levetiracetam composition of claim 1 , wherein the composition has a uniformity of blend, such that an assay of the blend is greater than 98 percent with an associated RSD of less than 1 percent.
5. The substantially glidant free levetiracetam composition of claim 1 , wherein the levetiracetam is present in an amount of at least about 60 percent by weight, based on the total weight of the composition.
6. The substantially glidant free levetiracetam composition of claim 1 , wherein the levetiracetam is present in an amount of at least about 70 percent by weight, based on the total weight of the composition.
7. The substantially glidant free levetiracetam composition of claim 1 , wherein the levetiracetam is present in an amount of from about 70 to about 95 percent by weight, based on the total weight of the composition.
8. The substantially glidant free levetiracetam composition of claim 1 , wherein the excipient is selected from the group consisting of corn starch, povidone, croscarmellose sodium, sodium starch glycolate, magnesium stearate, hydroxypropyl methylcellulose, polyethylene glycol, titanium dioxide, a coloring agent, and mixtures thereof.
9. The substantially glidant free levetiracetam composition of claim 1 , wherein particles of levetiracetam in the composition have a particle size distribution such that d(0.1) is not less than about 0.6 μm, d(0.5) is between about 10 and about 30 μm, and d(0.9) is not more than about 65 μm.
10. A pharmaceutical composition, comprising levetiracetam and, optionally, an excipient, wherein the composition is substantially free of any extra-granular glidant.
11. A pharmaceutical dosage form, comprising the pharmaceutical composition of claim 10 .
12. The pharmaceutical dosage form of claim 11 , wherein the dosage form is a tablet or capsule.
13. The pharmaceutical dosage form of claim 11 , comprising at least about 250 mg of levetiracetam.
14. A method of preparing a substantially glidant free levetiracetam pharmaceutical composition, the method comprising granulating a levetiracetam composition, thereby forming a granulated levetiracetam composition, and, optionally, blending the levetiracetam composition with one or more excipients, wherein the resulting pharmaceutical levetiracetam composition is substantially free of any extra-granular glidant.
15. The method of claim 14 , wherein the levetiracetam composition comprises at least one excipient.
16. The method of claim 14 , wherein the granulating comprises wet granulation.
17. The method of claim 16 , wherein the levetiracetam composition is granulated in a granulation liquid of purified water.
18. The method of claim 16 , further comprising compressing the pharmaceutical levetiracetam composition into a tablet, or placing the composition into a capsule.
19. The method of claim 16 , further comprising drying, milling, and, optionally, blending the granulated composition with one or more excipients; and compressing the substantially glidant free levetiracetam composition into a tablet, or placing the substantially glidant free levetiracetam composition into a capsule.
20. The method of claim 14 , wherein the granulating comprises dry granulation.
21. The method of claim 20 , further comprising compressing the levetiracetam composition into a tablet, or placing the composition into a capsule.
22. The method of claim 20 , further comprising milling and, optionally, blending the granulated composition with one or more excipients; and compressing the levetiracetam composition into a tablet, or placing the levetiracetam composition into a capsule.
23. The method of claim 14 , wherein particles of levetiracetam in the pharmaceutical composition have a particle size distribution such that d(0.1) is not less than about 0.6 μm; d(0.5) is between about 10 and about 30 μm, and d(0.9) is not more than about 65 μm.
Priority Applications (1)
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US11/371,128 US20070172521A1 (en) | 2006-01-24 | 2006-03-07 | Levetiracetam formulations and methods for their manufacture |
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US76210306P | 2006-01-24 | 2006-01-24 | |
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US (1) | US20070172521A1 (en) |
EP (1) | EP1810676B1 (en) |
JP (1) | JP2009524658A (en) |
CN (1) | CN101360493A (en) |
AT (1) | ATE413875T1 (en) |
CA (1) | CA2637925A1 (en) |
DE (1) | DE602006003617D1 (en) |
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ES (1) | ES2317452T3 (en) |
IL (1) | IL193024A0 (en) |
PL (1) | PL1810676T3 (en) |
PT (1) | PT1810676E (en) |
WO (1) | WO2007086891A1 (en) |
Cited By (3)
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US20100159009A1 (en) * | 2008-12-24 | 2010-06-24 | Zhongshui Yu | Controlled-release formulations |
US20100172979A1 (en) * | 2008-12-24 | 2010-07-08 | Zhongshui Yu | Controlled-release formulations |
US20110288138A1 (en) * | 2010-05-21 | 2011-11-24 | Sanovel llac Sanayi Ve Ticaret Anonim Sirketi | Orally disintegrating tablets of zolmitriptan and process for preparing the same |
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CA2696977C (en) | 2007-10-16 | 2012-12-04 | Pharmathen S.A. | Improved pharmaceutical composition containing a pyrrolidone anticonvulsant agent and method for the preparation thereof |
WO2009069089A1 (en) * | 2007-11-29 | 2009-06-04 | Ranbaxy Laboratories Limited | Levetiracetam controlled release composition |
EP2291177A2 (en) * | 2008-05-05 | 2011-03-09 | Farmaprojects, S.A. | Stable pharmaceutical compositions and their processes for preparation suitable for industrial scale |
PT2477611T (en) | 2009-09-18 | 2017-06-05 | Sanofi Sa | (z)-2-cyano-3-hydroxy-but-2-enoic acid-(4'-trifluormethylphenyl)-amide tablet formulations with improved stability |
CN101693017B (en) * | 2009-10-28 | 2012-06-06 | 北京赛科药业有限责任公司 | Medicament composition of levetiracetam and preparation process |
WO2011136751A2 (en) | 2010-04-26 | 2011-11-03 | Mahmut Bilgic | Water soluble pharmaceutical composition |
CN102379857B (en) * | 2011-05-30 | 2013-10-09 | 深圳信立泰药业股份有限公司 | Levetiracetam slow release medicinal composition and preparation method thereof |
CN102764254B (en) * | 2012-05-16 | 2016-09-07 | 深圳信立泰药业股份有限公司 | A kind of levetiracetam medicinal composition and preparation method thereof |
JP6630229B2 (en) * | 2016-05-17 | 2020-01-15 | エルメッド株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same |
JP6422464B2 (en) * | 2016-05-19 | 2018-11-14 | エルメッド エーザイ株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same, method for preventing delay of dissolution and / or dissolution of levetiracetam-containing pharmaceutical composition, and agent for preventing delay and / or dissolution of levetiracetam-containing pharmaceutical composition |
JP6326114B2 (en) * | 2016-11-01 | 2018-05-16 | エルメッド エーザイ株式会社 | Levetiracetam-containing pharmaceutical composition and method for producing the same, method for preventing delay of dissolution and / or dissolution of levetiracetam-containing pharmaceutical composition, and agent for preventing delay and / or dissolution of levetiracetam-containing pharmaceutical composition |
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- 2006-03-07 WO PCT/US2006/008298 patent/WO2007086891A1/en active Application Filing
- 2006-03-07 DK DK06251210T patent/DK1810676T3/en active
- 2006-03-07 CN CNA2006800516061A patent/CN101360493A/en active Pending
- 2006-03-07 EP EP06251210A patent/EP1810676B1/en not_active Revoked
- 2006-03-07 PL PL06251210T patent/PL1810676T3/en unknown
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Also Published As
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WO2007086891A1 (en) | 2007-08-02 |
JP2009524658A (en) | 2009-07-02 |
CN101360493A (en) | 2009-02-04 |
DE602006003617D1 (en) | 2008-12-24 |
IL193024A0 (en) | 2009-02-11 |
ES2317452T3 (en) | 2009-04-16 |
EP1810676B1 (en) | 2008-11-12 |
DK1810676T3 (en) | 2009-02-09 |
CA2637925A1 (en) | 2007-08-02 |
ATE413875T1 (en) | 2008-11-15 |
PT1810676E (en) | 2009-01-02 |
PL1810676T3 (en) | 2009-04-30 |
EP1810676A1 (en) | 2007-07-25 |
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